medicina Review Oral and Maxillo-Facial Manifestations of Systemic Diseases: An Overview Saverio Capodiferro *,† , Luisa Limongelli *,† and Gianfranco Favia Department of Interdisciplinary Medicine, University of Bari Aldo Moro, Piazza G. Cesare, 11, 70124 Bari, Italy; [email protected] * Correspondence: [email protected] (S.C.); [email protected] (L.L.) † These authors contributed equally to the paper. Abstract: Many systemic (infective, genetic, autoimmune, neoplastic) diseases may involve the oral cavity and, more generally, the soft and hard tissues of the head and neck as primary or secondary localization. Primary onset in the oral cavity of both pediatric and adult diseases usually represents a true challenge for clinicians; their precocious detection is often difficult and requires a wide knowledge but surely results in the early diagnosis and therapy onset with an overall better prognosis and clinical outcomes. In the current paper, as for the topic of the current Special Issue, the authors present an overview on the most frequent clinical manifestations at the oral and maxillo-facial district of systemic disease. Keywords: oral cavity; head and neck; systemic disease; oral signs of systemic diseases; early diagnosis; differential diagnosis Citation: Capodiferro, S.; Limongelli, 1. Introduction L.; Favia, G. Oral and Maxillo-Facial Oral and maxillo-facial manifestations of systemic diseases represent an extensive and Manifestations of Systemic Diseases: fascinating study, which is mainly based on the knowledge that many signs and symptoms An Overview. Medicina 2021, 57, 271. as numerous systemic disorders may first present as or may be identified by head and https://doi.org/10.3390/ neck tissue changes. Dentists and general practitioners play a key role in such early medicina57030271 identification; therefore, the clinical examination of the oral cavity should be performed accurately avoiding unexplored sites and a detailed medical history mandatorily collected. Academic Editor: Chung H. Kau Doubtful lesions of the oral mucosa, lip, skin of the face and neck, neck and sub-mandibular swellings, atypical radiological images or occasionally founded, atypical coloration and Received: 12 February 2021 forms of the teeth, unexplained and/or sudden mobility of one or more teeth, unexplained Accepted: 12 March 2021 bleeding from gingiva, oral mucosa and nose must be always careful investigated and Published: 16 March 2021 monitored to achieve a medical explanation. A cytological scrape or an incisional biopsy of suspicious lesions or a fine needle aspiration of doubtful swellings with subsequent Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in cyto-histological examination must be performed whenever deemed necessary to obtain a published maps and institutional affil- definitive diagnosis. iations. We review the most common and changeling oral and maxillo-facial findings possibly associated to or manifested at the onset of systemic diseases in adult and pediatric patients, along with diagnostic criteria and indications about differential diagnoses. 2. Infectious Diseases Copyright: © 2021 by the authors. Actinomycosis is an infrequent bacterial chronic infection and the disease most misdi- Licensee MDPI, Basel, Switzerland. This article is an open access article agnosed by experienced clinicians too. It is sustained by Actimomyces (mostly Actinomyces distributed under the terms and israelii or naeslundii), a saprophytic component of the endogenous flora of the oral cavity, conditions of the Creative Commons and is anatomically and clinically divided into three types; cervico-facial, pulmonary, Attribution (CC BY) license (https:// and abdominal-pelvic [1,2]. The cervicofacial type is the most frequent and may cause, creativecommons.org/licenses/by/ especially in immunocompromised individuals, suppurative and granulomatous inflam- 4.0/). matory lesions, with a locally aggressive and destructive behavior [3,4]. Soft tissue swelling Medicina 2021, 57, 271. https://doi.org/10.3390/medicina57030271 https://www.mdpi.com/journal/medicina Medicina 2021, 57, 271 2 of 22 (Figure1) or osteomyelitis with pus discharge, sinus tract formation are common clinical findings, resembling the classical symptoms of abscesses, acute sialoadenitis and lymphoad- enitis. Periapical localization may look like conventional periapical lesions (granuloma, cysts) in an x-ray, but it remains essentially unresponsive to medical and instrumental treatments. Microbiological cultures and histopathology are mandatory for diagnosis of this disease which, if untreated, may develop pulmonary, intracranial and para-pharyngeal diffusion [3–5]. Figure 1. Tongue swelling with pus discharge diagnosed as actimomycosis by a fine needle/core needle biopsy. Tuberculosis is a chronic granulomatous disease, typically of the lungs, but potentially involving multiple body systems, with the higher prevalence in developing countries or among immunocompromised patients, which carries a substantial rate of mortality [6]. Extra-pulmonary involvement mainly occurs due to endogenous spread of the pathogen from the primary site. The primary form arises from direct inoculation of the infecting pathogens in the susceptible sites in absence of systemic involvement, like in soft tissues of the oral cavity and the jawbone, mostly the mandible, where possible routes of infection are both sites of recent dental extraction, mucosal wounds or lacerations, and systemic hematogenous and/or lymphatic spread [7]. Clinically, tuberculosis may resemble peri- odontal or periapical lesions or abscesses with or without intra- or extra-oral draining, or as an impressive ulceration of oral mucosa associated or not to cervical lymphadenopa- thy [6–8]. Human immunodeficiency virus infection is nowadays the fourth leading cause of death worldwide [9] and oral manifestations are frequently the earliest signs, especially in unaware patients or detectable in 30%–80% of already diagnosed patients [9,10]. Oro- pharyngeal candidiasis and hairy leukoplakia are the most common early findings in undiagnosed cases [11–13]. Also, oro-maxillo-facial signs may include manifestations of bacterial, viral and fungal infections (mostly sustained by Mycobacterium, HPV, HSVs, CMV, Cryotococcus, Histoplasma, Aspergillus, Mucoraceae, etc.), (Figure2a–d) pseudo- tumoral lesions (necrotizing gingivitis or periodontitis, uni/bilateral lympho-epithelial cyst of the major salivary glands, cancrum oris, etc.), and also neoplasms (Kaposi’s sarcoma and Non-Hodgkin’s lymphoma) (Figure2e) [ 14–17]. Although the overall incidence of such manifestations has strongly decreased with the introduction of HAART therapy, a periodic examination of the mouth of infected patients is strongly suggested for a careful control of the disease. Medicina 2021, 57, 271 3 of 22 Figure 2. (a–e) Oral candidiasis of the median tongue (a), diffuse (b) or oro-pharingeal are frequent the first sign of HIV infection in unaware patients, as well Herpetic lesion of long-lasting duration occurring in un-conventional site, like the palate (c). Non-Hodgkin’s lymphoma of the palate in an already diagnosed HIV-patient. Human papillomavirus infection may cause several benign clinically papillary lesions in the oral cavity, such as squamous papilloma, (Figure3a,b) condyloma acuminatum, verruca vulgaris, and multifocal epithelial hyperplasia (Heck’s disease), and also it could be associated to the occurrence of potentially malignant lesions and oro-pharyngeal squa- mous cell carcinoma [18–24]. Over two hundred human papillomaviruses may be spread vertically (maternal-fetal transmission), horizontally (between individuals by sexual, skin- to-skin, skin-to-mucosa, or mucosa-to-mucosa transmission) and by autoinoculation [25]. Virus penetration may surely be facilitated by mucosal breakings or micro-abrasions with the following infection of the basilar stem cells, which subsequently differentiate in ker- atinocyte with contextual genoma amplification, evasion of the immune system and virus diffusion by desquamation from the upper layers [25–27]. The clinical and differential diagnosis between squamous papilloma, condyloma acuminatum, verruca vulgaris is quite 1 simple, but it mandatorily include giant cell fibroma, verruciform xanthoma, papillary squamous cell carcinoma, sialoadenoma papilliferum [28–32]. The diagnosis of multifocal epithelial hyperplasia is usually guided by clinical detection especially in children but, Cowden’s syndrome, neurofibromatosis type-1 and multiple endocrine neoplasia type 2B should always be considered in the differential diagnosis, along with the other benign clinically papillary lesions of the oral mucosa. Figure 3. (a,b) Single (a) and diffuse (b) lesions of the palate related to Human Papillomavirus infection. Medicina 2021, 57, 271 4 of 22 Epstein–Barr virus (EBV) infection usually occurs at an early age and, as for all human herpesviruses of which EBV is referred to as HHV-4, is generally characterized by a viral latency in the B-cells of most adults after initial infection [32–34]. EBV causes infectious mononucleosis, hairy leukoplakia (Figure4) also in healthy individuals, and, by a still not well defined tumorigenesis pathway of human oral epithelial or lymphoid tissue, several epithelial and non-epithelial neoplasms or tumor-like lesions in the head and neck, mostly in immunocompromised patients (such as Burkitt’s lymphoma, Hodgkin’s and non-Hodgkin’s lymphoma in immunodeficiency, post-transplant